Genetic variation of CYP3A and its influence on the pharmacokinetics of tacrolimus, a calcineurin inhibitor
Keywords:Pharmacogenetics, Tacrolimus, Calcineurin inhibitor, Renal transplant
Background: Tacrolimus (Tac) a calcineurin inhibitor (CNI), is a potent immunosuppressive drug which is widely used in organ transplant recipients. The drug has a narrow therapeutic window and high inter-individual pharmacokinetic variability. Tac is metabolized by cytochrome P450 3A (CYP3A) enzymes. The CYP3A5 activity is largely determined by the single nucleotide variant (SNV) CYP3A5*3 (c.219-237A>G; rs776746), which results in alternate mRNA splicing and a non-functional protein.
Methods: An observational prospective study was carried out at nephrology centre of army hospital where the consenting patients were enrolled in the study. The whole blood sample drawn was utilized to analyze for plasma drug concentration of Tac and genotyping for the CYP3A*5 polymorphism by the method as described by Cheung et al.
Results: 100 patients participated with an average of 98±8 days after transplantation. Recipients having heterozygous CYP3A5*1 genotype manifested 70% lower mean steady state concentration of Tac (C0/D ratio) 1.67±0.43 μg*l-1/mg in comparison to homozygote carriers of CYP3A5*3 5.60±1.94 μg*l-1/mg p<0.001.
Conclusions: Study suggested that Indian sub population closely mimics Caucasian population in terms of genotype expression for CYP3A5*3, who are expressing a non-functional enzyme for metabolism. Also, this study reinforces that population genotype CYP3A5*1 is significantly associated with lower C0/D ratio for Tac than the ones expressing homozygous CYP3A5*3 genotype. It also established the importance of pre-transplant genotyping, for better individualization of Tac doses. Further studies are suggested for population pharmacokinetic modelling study in future to derive starting dosage of Tac based on profiling of CYP3 genetics in recipients.
Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, et al. FK506, a novel immunosuppressant isolated from a Streptomyces I. Fermentation, isolation, and physio-chemical and biological characteristics. J Antibiot (Tokyo). 1987;40(9):1249-55.
Wallemacq PE, Reding R. FK506 (tacrolimus), a novel immunosuppressant in organ transplantation: clinical, biomedical, and analytical aspects. Clin Chemis. 1993;39:2219–28.
Scott LJ, McKeage K, Keam SJ, Plosker GL. Tacrolimus: a further update of its use in the management of organ transplantation. Drugs. 2003;63(12):1247-97.
Venkataramanan R, Swaminathan A, Prasad T, Jain A, Zuckerman S, Warty V, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29:404–30.
Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623-53.
Wallemacq P, Armstrong VW, Brunet M, Haufroid V, Holt DW, Johnston A, et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit. 2009;31(2):139-52.
Barraclough KA, Isbel NM, Kirkpatrick CM, Lee KJ, Taylor PJ, Johnson DW, et al. Evaluation of limited sampling methods for estimation of tacrolimus exposure in adult kidney transplant recipients. Br J Clin Pharmacol. 2011;71(2):207–23.
Katsakiori PF, Papapetrou EP, Sakellaropoulos GC, Goumenos DS, Nikiforidis GC, Christodoulos, et al. Factors affecting the long-term response to tacrolimus in renal transplant patients: Pharmacokinetic Pharmacogenetic approach. Int J Med Sci. 2010;7(2):94–100.
deJonge H, Kuypers DR. Pharmacogenetics in solid organ transplantation:current status and future directions. Transplant Rev. (Orlando). 2008;22(1):6-20.
Jusko WJ, Thomson AW, Fung J, McMaster P, Wong SH, Zylber-Katz E, et al. Consensus document:Therapeutic monitoring of tacrolimus (FK506). Ther Drug Monit. 1995;17(6):606-14.
Lamba J, Hebert JM, Schuetz EG, Kleinb TE, Altman RB. Pharm GKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics. 2012;22(7):555–8.
Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2002;54(10):1271-94.
Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383–91.
Lee SJ, Usmani KA, Chanas B, Ghanayem B, Xi T, Hodgson E, et al. Genetic findings and functional studies of human CYP3A5 single nucleotide polymorphisms in different ethnic groups. Pharmacogenetics. 2003;13:461–472.
Thompson EE, Kuttab-Boulos H, Witonsky D, Yang L, Roe BA, Di Rienzo A. CYP3A variation and the evolution of salt-sensitivity variants. Am J Hum Genet. 2004;75:1059–69.
Evans WE. Pharmacogenomics: marshalling the human genome to individualize drug therapy. Evans WE. Pharmacogenomics: marshalling the human genome to individualise drug therapy. Gut. 2003;52(2):10-8.
MacPhee IA, Holt DW. A pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype. Transplantation. 2008;85:163-5.
Passey C, Birnbaum AK, Brundage RC, Oetting WS, Israni AK, Jacobson PA. Dosing equation for tacrolimus using genetic variants and clinical factors. Br J Clin Pharmacol. 2011;72:948–57.
Lunde I, Bremer S, Midtvedt K, Mohebi B, Dahl M, Bergan S, et al. The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. Eur J Clin Pharmacol. 2014;70(6):685–93.
Thervet E, Loriot MA, Barbier S, Buchler M, Ficheux M, Choukroun G, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther. 2010;87:721–6.
Kurzawski M, Malinowski D, Dziewanwski K, Drozdzik M. Pharmacogenet. Genomics. 2014;24(8):397-400.
Bruckmueller H1, Werk AN, Renders L, Feldkamp T, Tepel M, Borst C, et al. Drug Monit. 2015;37(3):288-95.
Roy JN, Lajoie J, Zijenah LS, Barama A, Poirier C, Ward BJ, et al. CYP3A5 genetic polymorphisms in different ethnic populations. Drug Metab Dispos. 2005;33(7):884-7.
Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 2011;11(4):274-86.
Klein K, Thomas M, Winter S, Nussler AK, Niemi M, Schwab M, et al. PPARA: a novel genetic determinant of CYP3A4 in vitro and in vivo. Clin Pharmacol Ther. 2012;91(6):1044-52.
Elens L, Hesselink DA, Bouamar R, Budde K, de Fijter JW, De Meyer M, et al. Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients. Ther Drug Monit. 2014;36(1):71-9.